Many cellular events that lead to cancer and the progression of human disease represent aberrant gene expression and transcription. Our goal is to design molecules that can be programmed to bind with high affinity and specificity to a broad repertoire of DMA sites, permeate living human cells, traffic to the nucleus, bind DMA on chromatin and modulate transcription. The specific aims are to invent chemically robust heterocycles for minor groove recognition, explore new chemistry for targeting DMA in a chromatin context, explore chemistry for template-mediated ligation of modular units on the nucleosome core particle, exploit beta-linked polyamides for targeting purine tracts of GAA repeats to reverse the transcription inhibition of frataxin gene expression in Friedreich's Ataxia disease, and image the kinetics and organ distribution of [F- 18] labeled polyamides in living mice by positron emission tomography (PET) scanning. The long term goals of this program are to understand how these small molecules interact with the transcriptional machinery in cells in order to externally control and reprogram gene expression. To achieve these goals, the research program combines synthetic organic chemistry (with an emphasis on heterocycles), biophysical chemistry (quantitative footprinting titration, gel mobility shift assays), cell biology (confocal microscopy, qRT-PCR/mRNA, microarray analysis of global gene expression). Although gene regulation studies in small animals are planned, our efforts are not simply aimed at medicinal chemistry. Our studies also contribute to the basic biology of gene regulation in eukaryotic cells, and the potential therapeutic value of small molecule regulation of gene expression. Much needs to be learned about chromatin and promoter accessibility before DNA-targeted therapeutics are realized and it is our goal to contribute to this basic knowledge through our studies with programmable DMA binding oligomers. The ability to control gene expression by cell permeable small molecules would have profound implications for human medicine.